Publications by authors named "Michael Moran"

161 Publications

Isolating the impact of COVID-19 lockdown measures on urban air quality in Canada.

Air Qual Atmos Health 2021 May 18:1-22. Epub 2021 May 18.

Air Quality Research Division, Environment and Climate Change Canada, Toronto, Ontario Canada.

We have investigated the impact of reduced emissions due to COVID-19 lockdown measures in spring 2020 on air quality in Canada's four largest cities: Toronto, Montreal, Vancouver, and Calgary. Observed daily concentrations of NO, PM, and O during a "pre-lockdown" period (15 February-14 March 2020) and a "lockdown" period (22 March-2 May 2020), when lockdown measures were in full force everywhere in Canada, were compared to the same periods in the previous decade (2010-2019). Higher-than-usual seasonal declines in mean daily NO were observed for the pre-lockdown to lockdown periods in 2020. For PM, Montreal was the only city with a higher-than-usual seasonal decline, whereas for O all four cities remained within the previous decadal range. In order to isolate the impact of lockdown-related emission changes from other factors such as seasonal changes in meteorology and emissions and meteorological variability, two emission scenarios were performed with the GEM-MACH air quality model. The first was a Business-As-Usual (BAU) scenario with baseline emissions and the second was a more realistic simulation with estimated COVID-19 lockdown emissions. NO surface concentrations for the COVID-19 emission scenario decreased by 31 to 34% on average relative to the BAU scenario in the four metropolitan areas. Lower decreases ranging from 6 to 17% were predicted for PM. O surface concentrations, on the other hand, showed increases up to a maximum of 21% close to city centers versus slight decreases over the suburbs, but O (odd oxygen), like NO and PM, decreased as expected over these cities.

Supplementary Information: The online version contains supplementary material available at 10.1007/s11869-021-01039-1.
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http://dx.doi.org/10.1007/s11869-021-01039-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130219PMC
May 2021

Avelumab and cetuximab as a therapeutic combination: An overview of scientific rationale and current clinical trials in cancer.

Cancer Treat Rev 2021 Jun 2;97:102172. Epub 2021 Mar 2.

Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Treatment outcomes have improved with the advent of immune checkpoint inhibitors and small molecule inhibitors. However, many patients do not respond with single agents. Consequently, ongoing research is focused on the use of combination therapies to increase clinical efficacy by potential synergistic effects. Here, we outline ongoing trials and review the rationale and evidence for the combination of avelumab, an anti-programmed death ligand 1 (PD-L1) immunoglobulin G1 (IgG1) monoclonal antibody (mAb), with cetuximab, an anti-epidermal growth factor receptor (EGFR) IgG1 mAb. Avelumab is approved as a monotherapy for the treatment of Merkel cell carcinoma and urothelial carcinoma, and in combination with axitinib for renal cell carcinoma; cetuximab is approved in combination with chemotherapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN) and RAS wild-type metastatic colorectal cancer, and in combination with radiation therapy for SCCHN. Avelumab binds to PD-L1 expressed on tumor cells and immune regulatory cells, thus blocking its interaction with programmed death 1 and reventing T-cell suppression; cetuximab inhibits the EGFR signaling pathway, inhibiting proliferation and inducing apoptosis. Both therapies have complementary mechanisms of action and may also activate the immune system to induce innate effector function through the binding of their Fc regions to natural killer (NK) cells. Furthermore, cetuximab combined with chemotherapy has been shown to induce immunogenic cell death and leads to an increase in tumor-infiltrating CD8+ T and NK cells, which should synergize with the immunostimulatory effects of avelumab. Prospective studies will investigate this combination and inform future treatment strategies.
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http://dx.doi.org/10.1016/j.ctrv.2021.102172DOI Listing
June 2021

Stereotactic Radiosurgery for Differentiated Thyroid Cancer Brain Metastases: An International, Multicenter Study.

Thyroid 2021 May 11. Epub 2021 May 11.

Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA.

Brain metastases (BM) from differentiated thyroid cancer are rare. Stereotactic radiosurgery (SRS) is commonly used for the treatment of BMs; however, the experience with SRS for thyroid cancer BMs remains limited. The goal of this international, multi-centered study was to evaluate the efficacy and safety of SRS for thyroid cancer BMs. From 10 institutions participating in the International Radiosurgery Research Foundation, we pooled patients with established papillary or follicular thyroid cancer diagnosis who underwent SRS for histologically confirmed or radiologically suspected BMs. We investigated patient overall survival (OS), local tumor control, and adverse radiation events (AREs). We studied 42 (52% men) patients who underwent SRS for 122 papillary (83%) or follicular (17%) thyroid cancer BMs. The mean age at SRS was 59.86 ± 12.69 years. The mean latency from thyroid cancer diagnosis to SRS for BMs was 89.05 ± 105.49 months. The median number of BMs per patient was 2 (range: 1-10 BMs). The median SRS treatment volume was 0.79 cm (range: 0.003-38.18 cm), and the median SRS prescription dose was 20 Gy (range: 8-24 Gy). The median survival after SRS for BMs was 14 months (range: 3-58 months). The OS was significantly shorter in patients harboring ≥2 BMs, when compared with patients with one BM (Log-rank = 5.452,  = 0.02). Two or more BMs (odds ratio [OR] = 3.688; confidence interval [CI]: 1.143-11.904;  = 0.03) and lower Karnofsky performance score at the time of SRS (OR = 0.807; CI: 0.689-0.945;  = 0.008) were associated with shorter OS. During post-SRS imaging follow-up of 25.21 ± 30.49 months, local failure (progression and/or radiation necrosis) of BMs treated with SRS was documented in five (4%) BMs at 7.2 ± 7.3 months after the SRS. At the last imaging follow-up, the majority of patients with available imaging data had stable intracranial disease (33%) or achieved complete (26%) or partial (24%) response. There were no clinical AREs. Post-SRS peritumoral T2/fluid attenuated inversion recovery signal hyperintensity was noted in 7% BMs. The SRS allows durable local control of papillary and follicular thyroid cancer BMs in the vast majority of patients. Higher number of BMs and worse functional status at the time of SRS are associated with shorter OS in patients with thyroid cancer BMs. The SRS is safe and is associated with a low risk of AREs.
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http://dx.doi.org/10.1089/thy.2020.0947DOI Listing
May 2021

Discovery of a Low Thermal Conductivity Oxide Guided by Probe Structure Prediction and Machine Learning.

Angew Chem Int Ed Engl 2021 May 5. Epub 2021 May 5.

Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK.

We report the aperiodic titanate Ba Y Ti O with a room-temperature thermal conductivity that equals the lowest reported for an oxide. The structure is characterised by discontinuous occupancy modulation of each of the sites and can be considered as a quasicrystal. The resulting localisation of lattice vibrations suppresses phonon transport of heat. This new lead material for low-thermal-conductivity oxides is metastable and located within a quaternary phase field that has been previously explored. Its isolation thus requires a precisely defined synthetic protocol. The necessary narrowing of the search space for experimental investigation was achieved by evaluation of titanate crystal chemistry, prediction of unexplored structural motifs that would favour synthetically accessible new compositions, and assessment of their properties with machine-learning models.
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http://dx.doi.org/10.1002/anie.202102073DOI Listing
May 2021

Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: the STAR-TOR registry.

Future Oncol 2021 Jun 16;17(18):2325-2338. Epub 2021 Mar 16.

University Hospital Muenster, 48149, Muenster, Germany.

Examine outcomes in sunitinib-treated patients by International Metastatic RCC Database Consortium (IMDC) or Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors. Patients enrolled in STAR-TOR registry (n = 327). End points included overall survival, progression-free survival and objective response rate. Overall survival was similar for IMDC 0 versus 1 (p = 0.238) or 2 versus ≥3 (p = 0.156), but different for MSKCC (0 vs 1, p = 0.037; 2 vs ≥3, p = 0.001). Progression-free survival was similar for IMDC 2 versus 3 (p = 0.306), but different for MSKCC (p = 0.009). Objective response rate was different for IMDC 1 (41.9%) and 2 (29.5%) and similar for MSKCC 1 (34.4%) and 2 (31.0%). Outcome data varied according to IMDC or MSKCC. MSKCC model accurately stratify patients into risk groups. NCT00700258 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-1020DOI Listing
June 2021

Content analysis of promotional material for asthma-related products and therapies on Instagram.

Allergy Asthma Clin Immunol 2021 Mar 8;17(1):26. Epub 2021 Mar 8.

Institute for Healthcare Delivery and Population Science, University of Massachusetts Medical School-Baystate, 3601 Main St, 3rd Floor, Springfield, MA, 01107, USA.

Background: Increasingly, social media is a source for information about health and disease self-management. We conducted a content analysis of promotional asthma-related posts on Instagram to understand whether promoted products and services are consistent with the recommendations found in the Global Initiative for Asthma (GINA) 2019 guidelines.

Methods: We collected every Instagram post incorporating a common, asthma-related hashtag between September 29, 2019 and October 5, 2019. Of these 2936 collected posts, we analyzed a random sample of 266, of which, 211 met our inclusion criteria. Using an inductive, qualitative approach, we categorized the promotional posts and compared each post's content with the recommendations contained in the 2019 GINA guidelines. Posts were categorized as "consistent with GINA" if the content was supported by the GINA guidelines. Posts that promoted content that was not recommended by or was unrelated to the guidelines were categorized as "not supported by GINA".

Results: Of 211 posts, 89 (42.2%) were promotional in nature. Of these, a total of 29 (32.6%) were categorized as being consistent with GINA guidelines. The majority of posts were not supported by the guidelines. Forty-one (46.1%) posts promoted content that was not recommended by the current guidelines. Nineteen (21.3%) posts promoted content that was unrelated to the guidelines. The majority of unsupported content promoted non-pharmacological therapies (n = 39, 65%) to manage asthma, such as black seed oil, salt-room therapy, or cupping.

Conclusions: The majority of Instagram posts in our sample promoted products or services that were not supported by GINA guidelines. These findings suggest a need for providers to discuss online health information with patients and highlight an opportunity for providers and social media companies to promote evidence-based asthma treatments and self-management advice online.
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http://dx.doi.org/10.1186/s13223-021-00528-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938386PMC
March 2021

SLAP2 Adaptor Binding Disrupts c-CBL Autoinhibition to Activate Ubiquitin Ligase Function.

J Mol Biol 2021 04 20;433(8):166880. Epub 2021 Feb 20.

The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Program in Cell Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada. Electronic address:

CBL is a RING type E3 ubiquitin ligase that functions as a negative regulator of tyrosine kinase signaling and loss of CBL E3 function is implicated in several forms of leukemia. The Src-like adaptor proteins (SLAP/SLAP2) bind to CBL and are required for CBL-dependent downregulation of antigen receptor, cytokine receptor, and receptor tyrosine kinase signaling. Despite the established role of SLAP/SLAP2 in regulating CBL activity, the nature of the interaction and the mechanisms involved are not known. To understand the molecular basis of the interaction between SLAP/SLAP2 and CBL, we solved the crystal structure of CBL tyrosine kinase binding domain (TKBD) in complex with SLAP2. The carboxy-terminal region of SLAP2 adopts an α-helical structure which binds in a cleft between the 4H, EF-hand, and SH2 domains of the TKBD. This SLAP2 binding site is remote from the canonical TKBD phospho-tyrosine peptide binding site but overlaps with a region important for stabilizing CBL in its autoinhibited conformation. In addition, binding of SLAP2 to CBL in vitro activates the ubiquitin ligase function of autoinhibited CBL. Disruption of the CBL/SLAP2 interface through mutagenesis demonstrated a role for this protein-protein interaction in regulation of CBL E3 ligase activity in cells. Our results reveal that SLAP2 binding to a regulatory cleft of the TKBD provides an alternative mechanism for activation of CBL ubiquitin ligase function.
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http://dx.doi.org/10.1016/j.jmb.2021.166880DOI Listing
April 2021

Eight-Year Estimates of Methane Emissions from Oil and Gas Operations in Western Canada Are Nearly Twice Those Reported in Inventories.

Environ Sci Technol 2020 12 10;54(23):14899-14909. Epub 2020 Nov 10.

Climate Research Division, Environment and Climate Change Canada, Toronto, Ontario M3H 5T4, Canada.

The provinces of Alberta and Saskatchewan account for 70% of Canada's methane emissions from the oil and gas sector. In 2018, the Government of Canada introduced methane regulations to reduce emissions from the sector by 40-45% from the 2012 levels by 2025. Complementary to inventory accounting methods, the effectiveness of regulatory practices to reduce emissions can be assessed using atmospheric measurements and inverse models. Total anthropogenic (oil and gas, agriculture, and waste) emission rates of methane from 2010 to 2017 in Alberta and Saskatchewan were derived using hourly atmospheric methane measurements over a six-month winter period from October to March. Scaling up the winter estimate to annual indicated an anthropogenic emission rate of 3.7 ± 0.7 MtCH/year, about 60% greater than that reported in Canada's National Inventory Report (2.3 MtCH). This discrepancy is tied primarily to the oil and gas sector emissions as the reported emissions from livestock operations (0.6 MtCH) are well substantiated in both top-down and bottom-up estimates and waste management (0.1 MtCH) emissions are small. The resulting estimate of 3.0 MtCH from the oil and gas sector is nearly twice that reported in Canada's National Inventory (1.6 MtCH).
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http://dx.doi.org/10.1021/acs.est.0c04117DOI Listing
December 2020

Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry.

Future Oncol 2020 Dec 6;16(35):2939-2948. Epub 2020 Oct 6.

Klinik für Urologie, Universitätsmedizin Göttingen, Göttingen, Germany.

Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5-13.6] months) versus nonusers (6.9 [5.7-8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9-28.3] months) versus nonusers (25.7 [22.7-33.0] months) (p = 0.0212). Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0548DOI Listing
December 2020

Recognition of typical antibiotic residues in environmental media related to groundwater in China (2009-2019).

J Hazard Mater 2020 11 29;399:122813. Epub 2020 May 29.

MOE Key Laboratory of Groundwater Circulation and Environmental Evolution, China University of Geosciences (Beijing), Beijing, PR China; Beijing Key Laboratory of Water Resources and Environmental Engineering, China University of Geosciences (Beijing), Beijing, PR China. Electronic address:

The potential adverse environmental and health-related impacts of antibiotics are becoming more and more concerning. China is globally the largest antibiotic producer and consumer, possibly resulting in the ubiquity and high detection levels of antibiotics in environmental compartments. Clear status on the concentration levels and spatial distribution of antibiotic contamination in China's environment is necessary to gain insight into the establishment of legal and regulatory frameworks. This study collects information from over 170 papers reporting the occurrence and distribution of antibiotics in China's environment. A total of 110 antibiotics were detected, and 28 priority antibiotics were ubiquitous in China in almost all compartments of the environment, excluding the atmosphere. Seven dominant antibiotics in all environment compartments were identified by cluster analysis, including tetracycline, oxytetracycline, chlortetracycline, ofloxacin, enrofloxacin, norfloxacin, and ciprofloxacin. Meanwhile, sulfamethoxazole, sulfadiazine, and sulfamethazine were also frequently found in aqueous phases. Among the main basins where antibiotics were detected, the Haihe River Basin had higher median antibiotic concentrations in surface water compared to other basins, while the Huaihe River Basin had higher median concentrations in sediment. The median values of antibiotic concentrations in the sources were as follows: animal manure, 39 μg/kg (microgram per kilogram); WWTP (wastewater treatment plant) sludge, 39 μg/kg; animal wastewater, 156 ng/L (nanogram per liter); WWTP effluent: 15 ng/L. These concentrations are 1 - 2 orders of magnitude higher than that of the receptors (soil, 2.1 μg/kg; sediment, 4.7 μg/kg; surface water, 8.1 ng/L; groundwater, 2.9 ng/L), whether in solid or aqueous phases. Based on the number of detected antibiotics in various environmental compartments, animal farms and WWTPs are the main sources of antibiotics, and surface water and sediment are the main receptors of antibiotics. Hierarchical clustering identified the two main pathways of antibiotic transfer in various environmental compartments, which are from animal wastewater/WWTP effluent to surface water/sediment and from animal manure/WWTP sludge to soil/groundwater.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122813DOI Listing
November 2020

Cancer proteome and metabolite changes linked to SHMT2.

PLoS One 2020 9;15(9):e0237981. Epub 2020 Sep 9.

Program in Cell Biology, The Hospital for Sick Children, Toronto, Canada.

Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237981PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480864PMC
October 2020

Development and pilot testing of an adaptable protocol to address postpartum depression in pediatric practices serving lower-income and racial/ethnic minority families: contextual considerations.

Implement Sci Commun 2020 21;1:66. Epub 2020 Jul 21.

Department of Psychiatry, University of Massachusetts Medical School-Worcester, 55 Lake Avenue N, Worcester, MA 01655 USA.

Background: Postpartum depression (PPD) affects approximately 25% of women in lower-income and racial/ethnic minority populations in the USA. Evidence-based interventions for PPD screening and treatment exist, but many women with PPD are not identified or are inadequately treated. To address this gap, the American Academy of Pediatrics recommends screening for PPD at routine preventive visits in the first 6 months of postpartum, but less than half of pediatricians do so. Small PPD screening studies have been conducted in pediatric practices serving average-risk women, but less is known about practices serving families with lower-income and/or racial/ethnic minority status (safety-net practices). Study objectives were (1) to develop and pilot test an adaptable PPD screening protocol in safety-net practices and (2) to test strategies for implementing the protocol.

Methods: The Consolidated Framework for Implementation Research was used for this two-phase pilot study. Phase I focus groups with pediatric providers and staff in four safety-net practices informed phase II development and implementation of a PPD screening and referral protocol. Feasibility measures included the percentage of eligible women screened and documentation of follow-up plans in the electronic health record at 1-, 2-, 4-, and 6-month preventive visits over 3 months. Implementation strategies were assessed for acceptability, appropriateness, and feasibility.

Results: Focus group participants felt that (1) addressing PPD in the pediatric setting is important, (2) all clinical team members should be engaged in screening, (3) workflows and competing interests may present barriers, and (4) commonly used screening tools/approaches may not adequately detect depression in the population studied. During protocol implementation, screening rates increased from 75 to 85% for 324 eligible preventive visits and documentation of follow-up plans increased from 66 to 87%. Only 6.5% of women screened positive (EPDS ≥ 10). Minor adaptations to implementation strategies were recommended to improve acceptability, appropriateness, and feasibility.

Conclusions: Although developing and implementing an adaptable protocol for PPD screening in safety-net pediatric practices using external facilitation and a bundle of implementation strategies appear feasible, low positive screen rates suggest adaptations to account for intersecting patient, practice, and external policy contexts are needed to improve PPD screening effectiveness in these practices.
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http://dx.doi.org/10.1186/s43058-020-00049-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427956PMC
July 2020

Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma.

Blood 2021 Mar;137(11):1478-1490

Guangzhou Institute of Cardiovascular Diseases, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Diseases, The Second Affiliated Hospital-Guangdong Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, People's Republic of China.

The oncogenic transcription factor c-Maf has been proposed as an ideal therapeutic target for multiple myeloma (MM), but how to achieve it is still elusive. In the present study, we found the Otub1/c-Maf axis could be a potential target. Otub1, an OTU family deubiquitinase, was found to interact with c-Maf by mass spectrometry. Otub1 abrogates c-Maf K48-linked polyubiquitination, thus preventing its degradation and enhancing its transcriptional activity. Specifically, this deubiquitinating activity depends on its Lys71 and the N terminus but is independent of UBE2O, a known E2 of c-Maf. Otub1 promotes MM cell survival and MM tumor growth. In contrast, silence of Otub1 leads to c-Maf degradation and c-Maf-expressing MM cell apoptosis. Therefore, the Otub1/c-Maf axis could be a therapeutic target of MM. In order to explore this concept, we performed a c-Maf recognition element-driven luciferase-based screen against US Food and Drug Administration-approved drugs and natural products, from which the generic cardiac glycoside lanatoside C (LanC) is found to prevent c-Maf deubiquitination and induces its degradation by disrupting the interaction of Otub1 and c-Maf. Consequently, LanC inhibits c-Maf transcriptional activity, induces c-Maf-expressing MM cell apoptosis, and suppresses MM growth and prolongs overall survival of model mice, but without apparent toxicity. Therefore, the present study identifies Otub1 as a novel deubiquitinase of c-Maf and establishes that the Otub1/c-Maf axis is a potential therapeutic target for MM.
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http://dx.doi.org/10.1182/blood.2020005199DOI Listing
March 2021

Data Dependent-Independent Acquisition (DDIA) Proteomics.

J Proteome Res 2020 08 15;19(8):3230-3237. Epub 2020 Jun 15.

David R. Cheriton School of Computer Science, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada.

Data dependent acquisition (DDA) and data independent acquisition (DIA) are traditionally separate experimental paradigms in bottom-up proteomics. In this work, we developed a strategy combining the two experimental methods into a single LC-MS/MS run. We call the novel strategy data dependent-independent acquisition proteomics, or DDIA for short. Peptides identified from DDA scans by a conventional and robust DDA identification workflow provide useful information for interrogation of DIA scans. Deep learning based LC-MS/MS property prediction tools, developed previously, can be used repeatedly to produce spectral libraries facilitating DIA scan extraction. A complete DDIA data processing pipeline, including the modules for iRT vs RT calibration curve generation, DIA extraction classifier training, and false discovery rate control, has been developed. Compared to another spectral library-free method, DIA-Umpire, the DDIA method produced a similar number of peptide identifications, but nearly twice as many protein group identifications. The primary advantage of the DDIA method is that it requires minimal information for processing its data.
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http://dx.doi.org/10.1021/acs.jproteome.0c00186DOI Listing
August 2020

Expansion of a size disaggregation profile library for particulate matter emissions processing from three generic profiles to 36 source-type-specific profiles.

J Air Waste Manag Assoc 2020 11;70(11):1067-1100

Air Quality Research Division, Environment and Climate Change Canada , Toronto, ON, Canada.

This study describes a significant upgrade to the particulate matter (PM) size disaggregation profile library used for preparing emissions files for the GEM-MACH (Global Environmental Multiscale-Modelling Air-quality and CHemistry) chemical transport model (CTM). This model uses a sectional (bin) approach to represent the PM size distribution, where one configuration employs 12 size bins to disaggregate PM and PM inventory emissions into the first 10 bins ranging from 0.01 to 10.24 μm in diameter. For the size disaggregation step, a small library of three generic PM size disaggregation profiles is currently applied for three broad source categories (area, mobile, and point). However, as might be expected, these generic profiles are not always representative: for example, emissions from two very different area sources ‒ paved road dust and residential wood combustion ‒ are disaggregated using the same generic size distribution profile. In order to improve the current small PM size disaggregation profile library, a comprehensive literature review was conducted: over 100 relevant publications were identified and PM size distribution profiles for 36 different emission source types were selected and compiled. These 36 source-type-specific PM size distribution profiles were then combined based on process type with corresponding PM speciation profiles to create a library of chemically speciated and size-resolved PM disaggregation profiles. This library can now be used by the SMOKE (Sparse Matrix Operator Kernel Emissions) emissions processing system for the 12-bin version of GEM-MACH to perform PM chemical speciation and size allocation in one step. The size-profile data collected and compiled in this study may also be used for emissions processing for other CTMs with a size-resolved representation of PM. Details of the compilation of the 36 PM size disaggregation profiles are discussed, and the differences in processed PM emissions based on the current and updated PM size disaggregation profile libraries are shown. : A new and expanded particulate matter (PM) size disaggregation profile library covering 36 emission source types has been developed based on an extensive literature review. Its use can produce significant changes in the size allocation of bulk PM inventory emissions processed for input to size-resolved PM chemical transport models. Such models are used to predict atmospheric visibility and to simulate the interactions of aerosol particles with atmospheric radiation and with clouds. The use of more accurate, size-resolved primary PM emissions by these models should improve their predictive skill for atmospheric PM processes affecting air quality, meteorology, and climate.
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http://dx.doi.org/10.1080/10962247.2020.1743794DOI Listing
November 2020

A drug discovery platform to identify compounds that inhibit EGFR triple mutants.

Nat Chem Biol 2020 05 24;16(5):577-586. Epub 2020 Feb 24.

Department for Lung Diseases Jordanovac, Clinical Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia.

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.
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http://dx.doi.org/10.1038/s41589-020-0484-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123931PMC
May 2020

Repeat-Preserving Decoy Database for False Discovery Rate Estimation in Peptide Identification.

J Proteome Res 2020 03 21;19(3):1029-1036. Epub 2020 Feb 21.

David R. Cheriton School of Computer Science, University of Waterloo, Waterloo N2L 3G1, Canada.

The sequence database searching method is widely used in proteomics for peptide identification. To control the false discovery rate (FDR) of the searching results, the target-decoy method generates and searches a decoy database together with the target database. A known problem is that the target protein sequence database may contain numerous repeated peptides. The structures of these repeats are not preserved by most existing decoy generation algorithms. Previous studies suggest that such discrepancy between the target and decoy databases may lead to an inaccurate FDR estimation. Based on the de Bruijn graph model, we propose a new repeat-preserving algorithm to generate decoy databases. We prove that this algorithm preserves the structures of the repeats in the target database to a great extent. The de Bruijn method has been compared with a few other commonly used methods and demonstrated superior FDR estimation accuracy and an improved number of peptide identification.
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http://dx.doi.org/10.1021/acs.jproteome.9b00555DOI Listing
March 2020

Top-Down Determination of Black Carbon Emissions from Oil Sand Facilities in Alberta, Canada Using Aircraft Measurements.

Environ Sci Technol 2020 01 20;54(1):412-418. Epub 2019 Dec 20.

National Research Council Canada, Flight Research Laboratory, Ottawa, Ontario K1A 0R6, Canada.

Black carbon (BC) emissions from the Canadian oil sand (OS) surface mining facilities in Alberta were investigated using aircraft measurements. BC emission rates were derived with a top-down mass balance approach and were found to be linearly related to the volume of oil sand ore mined at each facility. Two emission factors were determined from the measurements; production-based BC emission factors were in the range of 0.6-1.7 g/tonne mined OS ore, whereas fuel-based BC emission factors were between 95 and 190 mg/kg-fuel, depending upon the facility. The annual BC emission, at 707 ± 117 tonnes/year for the facilities, was determined using the production-based emission factors and annual production data. Although this annual emission is in reasonable agreement with the BC annual emissions reported in the latest version of the Canadian national BC inventory (within 16%), the relative split between off-road diesel and stack sources is significantly different between the measurements and the inventory. This measurement evidence highlights the fact that the stack sources of BC may be overestimated and the off-road diesel sources may be underestimated in the inventory and points to the need for improved BC emission data from diesel sources within facilities.
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http://dx.doi.org/10.1021/acs.est.9b05522DOI Listing
January 2020

The deubiquitinase USP7 stabilizes Maf proteins to promote myeloma cell survival.

J Biol Chem 2020 02 10;295(7):2084-2096. Epub 2019 Dec 10.

Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Guangzhou and Guangdong Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Xinzao Town, Panyu District, Guangzhou 511436, China; Guangzhou Institute of Cardiovascular Disease and Department of Hematology, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China. Electronic address:

The Maf proteins, including c-Maf, MafA, and MafB, are critical transcription factors in myelomagenesis. Previous studies demonstrated that Maf proteins are processed by the ubiquitin-proteasome pathway, but the mechanisms remain elusive. This study applied MS to identify MafB ubiquitination-associated proteins and found that the ubiquitin-specific protease USP7 was present in the MafB interactome. Moreover, USP7 also interacted with c-Maf and MafA and blocked their polyubiquitination and degradation. Consistently, knockdown of USP7 resulted in Maf protein degradation along with increased polyubiquitination levels. The action of USP7 thus promoted Maf transcriptional activity as evidenced by luciferase assays and by the up-regulation of the expression of Maf-modulated genes. Furthermore, USP7 was up-regulated in myeloma cells, and it was negatively associated with the survival of myeloma patients. USP7 promoted myeloma cell survival, and when it was inhibited by its specific inhibitor P5091, myeloma cell lines underwent apoptosis. These results therefore demonstrated that USP7 is a deubiquitinase of Maf proteins and promotes MM cell survival in association with Maf stability. Given the significance of USP7 and Maf proteins in myeloma genesis, targeting the USP7/Maf axle is a potential strategy to the precision therapy of MM.
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http://dx.doi.org/10.1074/jbc.RA119.010724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029123PMC
February 2020

Comparison of Molecular Assays for HPV Testing in Oropharyngeal Squamous Cell Carcinomas: A Population-Based Study in Northern Ireland.

Cancer Epidemiol Biomarkers Prev 2020 01 30;29(1):31-38. Epub 2019 Oct 30.

Northern Ireland Molecular Pathology Laboratory, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.

Background: Determination of human papillomavirus (HPV) status has become clinically relevant for patient stratification under UICC TNM8 staging. Within the United Kingdom, a combination of p16 IHC and HPV DNA-ISH is recommended for classifying HPV status. This study will assess a series of clinically applicable second-line molecular tests to run in combination with p16 IHC to optimally determine HPV status.

Methods: The ability of HPV RNA-ISH, HPV DNA-ISH, and HPV DNA-PCR to identify p16-positive/HPV-positive patients was investigated in a population-based oropharyngeal squamous cell carcinoma (OPSCC) cohort of patients diagnosed in Northern Ireland from 2000 to 2011.

Results: Only 41% of the Northern Irish OPSCC patient population was associated with HPV-driven carcinogenesis. Both ISH assays were more specific than the DNA-PCR assay (100% and 95% vs. 67%) and were less likely to be affected by preanalytic factors such as increasing block age. A pooled HPV genotype probe for RNA-ISH was found to be the most accurate molecular assay assessed (95% accuracy) when compared with p16 positivity.

Conclusions: Our study demonstrates the advantage of tissue-based molecular assays when determining HPV status in retrospective samples. Specifically, we demonstrate the enhanced sensitivity and specificity of ISH techniques compared with PCR-based methodology when working with formalin-fixed paraffin-embedded tissue, and found HPV RNA-ISH to be the most effective assay for determining HPV status.

Impact: As p16 IHC is a relatively inexpensive, accessible, and sensitive test for stratifying patients by HPV status, this study finds that more patients would benefit from first-line p16 IHC followed by specific HPV testing using HPV RNA-ISH to confirm HPV status.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0538DOI Listing
January 2020

Augmenting the randomized controlled trial with real-world data to aid clinical decision making in metastatic renal cell carcinoma: a systematic review and meta-analysis.

Future Oncol 2019 Dec 18;15(34):3987-4001. Epub 2019 Oct 18.

Cambridge University Hospital, Cancer Services, Cambridge, UK.

To evaluate how efficacy outcomes from real-world data (RWD) can support those from randomized controlled trials (RCTs), in the context of first-line tyrosine kinase inhibitor treatment of metastatic renal cell carcinoma. PubMed, Ovid, MEDLINE and EMBASE were searched for RCTs and RWD studies with ≥50 adult patients per arm published in 2000-2017. Outcome measures were median progression-free survival, median overall survival and objective response rate. A total of 13 RCTs and 22 RWD studies met eligibility criteria; 31, 28 and 25 studies, respectively, reported median progression-free survival, median overall survival and objective response rate. Summary outcome measures were similar in RWD and RCTs. RWD validates efficacy-based outcomes from RCTs and may provide supportive evidence to inform clinical decisions.
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http://dx.doi.org/10.2217/fon-2019-0421DOI Listing
December 2019

Extracellular phosphorylation drives the formation of neuronal circuitry.

Nat Chem Biol 2019 11 26;15(11):1035-1042. Epub 2019 Aug 26.

Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada.

Until recently, the existence of extracellular kinase activity was questioned. Many proteins of the central nervous system are targeted, but it remains unknown whether, or how, extracellular phosphorylation influences brain development. Here we show that the tyrosine kinase vertebrate lonesome kinase (VLK), which is secreted by projecting retinal ganglion cells, phosphorylates the extracellular protein repulsive guidance molecule b (RGMb) in a dorsal-ventral descending gradient. Silencing of VLK or RGMb causes aberrant axonal branching and severe axon misguidance in the chick optic tectum. Mice harboring RGMb with a point mutation in the phosphorylation site also display aberrant axonal pathfinding. Mechanistic analyses show that VLK-mediated RGMb phosphorylation modulates Wnt3a activity by regulating LRP5 protein gradients. Thus, the secretion of VLK by projecting neurons provides crucial signals for the accurate formation of nervous system circuitry. The dramatic effect of VLK on RGMb and Wnt3a signaling implies that extracellular phosphorylation likely has broad and profound effects on brain development, function and disease.
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http://dx.doi.org/10.1038/s41589-019-0345-zDOI Listing
November 2019

Somatic Alteration Burden Involving Non-Cancer Genes Predicts Prognosis in Early-Stage Non-Small Cell Lung Cancer.

Cancers (Basel) 2019 Jul 19;11(7). Epub 2019 Jul 19.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.

The burden of somatic mutations and neoantigens has been associated with improved survival in cancer treated with immunotherapies, especially non-small cell lung cancer (NSCLC). However, there is uncertainty about their effect on outcome in early-stage untreated cases. We posited that the burden of mutations in a specific set of genes may also contribute to the prognosis of early NSCLC patients. From a small cohort of 36 NSCLC cases, we were able to identify somatic mutations and copy number alterations in 865 genes that contributed to patient overall survival. Simply, the number of altered genes (NAG) among these 865 genes was associated with longer disease-free survival (hazard ratio (HR) = 0.153, = 1.48 × 10). The gene expression signature distinguishing patients with high/low NAG was also prognostic in three independent datasets. Patients with a high NAG could be further stratified based on the presence of immunogenic mutations, revealing a further subgroup of stage I NSCLC with even better prognosis (85% with >5 years survival), and associated with cytotoxic T-cell expression. Importantly, 95% of the highly-altered genes lacked direct relation to cancer, but were implicated in pathways regulating cell proliferation, motility and immune response.
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http://dx.doi.org/10.3390/cancers11071009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678704PMC
July 2019

Sunitinib for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World and Clinical Trials Data.

Target Oncol 2019 08;14(4):405-416

Cambridge University Hospital, Cambridge, UK.

Background: Randomized controlled trials (RCTs) have stringent inclusion criteria and may not fully represent patients seen in everyday clinical practice. Real-world data (RWD) can provide supportive evidence for the effectiveness of medical interventions in more heterogeneous populations than RCTs. Sunitinib is a widely used first-line treatment for patients with metastatic renal cell carcinoma (mRCC).

Objective: This is the first comprehensive meta-analysis to evaluate the efficacy of sunitinib using the novel approach of combining RCTs and RWD.

Methods: RCTs and RWD studies published between 2000 and 2017 were identified from PubMed, Ovid, MEDLINE, and EMBASE. Eligible studies contained a cohort of ≥ 50 adult patients with mRCC receiving first-line sunitinib treatment. The meta-analysis combined RWD and RCT treatment groups, adjusting for data type (RCT or RWD). Recorded outcomes were median progression-free survival (mPFS), median overall survival (mOS), and objective response rate (ORR). Publication bias was assessed via review of funnel plots for each outcome measure. A random effects model to account for study heterogeneity was applied to each endpoint. Sensitivity analyses evaluated the robustness of the overall estimates.

Results: Of the 3611 studies identified through medical database searches, 22 (15 RWD studies, 7 RCTs) met eligibility criteria and were analyzed. mPFS (18 studies), mOS (19 studies), and ORR (15 studies) were reported for aggregate measures based on 4815, 5321, and 4183 patients, respectively. Reported mPFS (RWD, 7.5-11.0 months; RCTs, 5.6-15.1 months) and ORR data (RWD, 14.0-34.6%; RCTs, 18.8-46.9%) were consistent with the overall confidence estimates (95% confidence interval [CI]) of 9.3 (8.6-10.2) months and 27.9% (24.2-32.0), respectively. Reported mOS showed greater variation in RWD (6.8-33.2 months) compared with RCTs (21.8-31.5 months), with an overall confidence estimate (95% CI) of 23.0 (19.2-27.6) months. Inspection of funnel plots and sensitivity analyses indicated that there was no publication bias for any efficacy endpoint. Sensitivity analyses showed no evidence of lack of robustness for mPFS, mOS, or ORR. Interpretation of these results is limited by differences in trial design, cohort characteristics, and missing data.

Conclusions: This novel, comprehensive meta-analysis validates sunitinib as an effective first-line treatment for patients with mRCC in both RCTs and everyday clinical practice. The methodology provides a framework for future analyses combining data from RCTs and RWD.
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http://dx.doi.org/10.1007/s11523-019-00653-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684538PMC
August 2019

ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma.

Cancer Res 2019 08 10;79(16):4057-4071. Epub 2019 Jul 10.

The Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, Canada.

Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma. SIGNIFICANCE: These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1357DOI Listing
August 2019

Prediction of LC-MS/MS Properties of Peptides from Sequence by Deep Learning.

Mol Cell Proteomics 2019 10 27;18(10):2099-2107. Epub 2019 Jun 27.

David R. Cheriton School of Computer Science, University of Waterloo, Waterloo, ON, N2L 3G1, Canada.

Deep learning models for prediction of three key LC-MS/MS properties from peptide sequences were developed. The LC-MS/MS properties or behaviors are indexed retention times (iRT), MS1 or survey scan charge state distributions, and sequence ion intensities of HCD spectra. A common core deep supervised learning architecture, bidirectional long-short term memory (LSTM) recurrent neural networks was used to construct the three prediction models. Two featurization schemes were proposed and demonstrated to allow for efficient encoding of modifications. The iRT and charge state distribution models were trained with on order of 10 data points each. An HCD sequence ion prediction model was trained with 2 × 10 experimental spectra. The iRT prediction model and HCD sequence ion prediction model provide improved accuracies over the start-of-the-art models available in literature. The MS1 charge state distribution prediction model offers excellent performance. The prediction models can be used to enhance peptide identification and quantification in data-dependent acquisition and data-independent acquisition (DIA) experiments as well as to assist MRM (multiple reaction monitoring) and PRM (parallel reaction monitoring) experiment design.
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http://dx.doi.org/10.1074/mcp.TIR119.001412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773555PMC
October 2019

Organizational characteristics associated with high performance on quality measures in pediatric primary care: A positive deviance study.

Health Care Manage Rev 2019 May 20. Epub 2019 May 20.

Sarah L. Goff, MD, PhD, is from Institute of Healthcare Delivery and Population Health Science and Associate Professor, Department of Medicine, University of Massachusetts Medical School-Baystate. E-mail: Kathleen M. Mazor, EdD, is Associate Director, Meyers Primary Care Institute, and Professor, Department of Medicine, University of Massachusetts Medical School-Worcester. Aruna Priya, MA, MSc, is from Biostatistics Core, Institute for Healthcare Delivery and Population Science, University of Massachusetts Medical School-Baystate. Michael Moran, BS, is Research Assistant, Institute for Healthcare Delivery and Population Science, University of Massachusetts Medical School-Baystate. Penelope S. Pekow, PhD, is Senior Biostatistician, Institute for Healthcare Delivery and Population Science, University of Massachusetts Medical School-Baystate, and Research Assistant Professor, School of Public Health and Health Sciences, University of Massachusetts-Amherst. Peter K. Lindenauer, MD, MSc, is Professor, Institute for Healthcare Delivery and Population Science, Department of Medicine, University of Massachusetts Medical School-Baystate, and Professor, Department of Quantitative Health Sciences, University of Massachusetts Medical School-Worcester.

Background: Pediatric health care quality in the United States varies, but the reasons for variation are not fully understood. Differences in pediatric practices' organizational characteristics, such as organizational structures, strategies employed to improve quality, and other contextual factors, may contribute to the variation observed.

Purpose: To assess the relationship between organizational characteristics and performance on clinical quality (CQ) and patient experience (PE) measures in primary care pediatric practices in Massachusetts.

Methodology: A 60-item questionnaire that assessed the presence of selected organizational characteristics was sent to 172 pediatric practice managers in Massachusetts between December 2017 and February 2018. The associations between select organizational characteristics and publicly available CQ and PE scores were analyzed using analysis of variance; open-ended survey questions were analyzed using qualitative content analysis.

Results: Eighty-six practices (50.0%) responded; 80 (46.5%) were included in the primary analysis. Having a quality champion (p = .03), offering co-located specialty services (e.g., behavioral health; p = .04), being a privately owned practice (p = .04), believing that patients and families feel respected (p = .03), and having a lower percentage of patients (10%-25%) covered by public health insurance (p = .04) were associated with higher CQ scores. Higher PE scores were associated with private practice ownership (p = .0006). Qualitative analysis suggested organizational culture and external factors, such as health care finance, may affect quality.

Conclusions: Both modifiable organizational practices and factors external to a practice may affect quality of care. Addressing differences in practice performance may not be reducible to implementation of changes in single organizational characteristics.

Practice Implications: Pediatric practices seeking to improve quality of care may wish to adopt the strategies that were associated with higher performance on quality measures, but additional studies are needed to better understand the mechanisms behind these associations and how they relate to each other.
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http://dx.doi.org/10.1097/HMR.0000000000000247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864254PMC
May 2019

Evosep One Enables Robust Deep Proteome Coverage Using Tandem Mass Tags while Significantly Reducing Instrument Time.

J Proteome Res 2019 05 12;18(5):2346-2353. Epub 2019 Apr 12.

Department of Molecular Genetics , University of Toronto , 1 King's College Circle , Toronto , ON , Canada M5S 1A8.

The balance between comprehensively analyzing the proteome and using valuable mass spectrometry time is a genuine challenge in the field of proteomics. Multidimensional fractionation strategies have significantly increased proteome coverage, but often at the cost of increased mass analysis time, despite advances in mass spectrometer acquisition rates. Recently, the Evosep One liquid chromatography system was shown to analyze peptide samples in a high-throughput manner without sacrificing in-depth proteomics coverage. We demonstrate the incorporation of Evosep One technology into our multiplexing workflow for analysis of tandem mass tag (TMT)-labeled nonsmall cell lung carcinoma (NSCLC) patient-derived xenografts (PDXs). By the use of a 30 samples per day Evosep workflow, >12 000 proteins were identified in 48 h of mass spectrometry time, which is comparable to the number of proteins identified by our conventional concatenated EASY-nLC workflow in 60 h. Shorter Evosep gradient lengths reduced the number of protein identifications by 10% while decreasing the mass analysis time by 50%. This Evosep workflow will enable quantitative analysis of multiplexed samples in less time without conceding depth of proteome coverage.
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http://dx.doi.org/10.1021/acs.jproteome.9b00082DOI Listing
May 2019

Recommendations for determining HPV status in patients with oropharyngeal cancers under TNM8 guidelines: a two-tier approach.

Br J Cancer 2019 04 20;120(8):827-833. Epub 2019 Mar 20.

Centre for Cell Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.

Background: TNM8 staging for oropharyngeal squamous cell carcinomas (OPSCC) surrogates p16 immunohistochemistry for HPV testing. Patients with p16+ OPSCC may lack HPV aetiology. Here, we evaluate the suitability of TNM8 staging for guiding prognosis in such patients.

Methods: HPV status was ascertained using p16 immunohistochemistry and high-risk HPV RNA and DNA in situ hybridisation. Survival by stage in a cohort of OPSCC patients was evaluated using TNM7/TNM8 staging. Survival of p16+/HPV- patients was compared to p16 status.

Results: TNM8 staging was found to improve on TNM7 (log rank p = 0·0190 for TNM8 compared with p = 0·0530 for TNM7) in p16+ patients. Patients who tested p16+ but were HPV- (n = 20) had significantly reduced five-year survival (33%) compared to p16+ patients (77%) but not p16- patients (35%). Cancer stage was reduced in 95% of p16+/HPV- patients despite having a mortality rate twice (HR 2.66 [95% CI: 1.37-5.15]) that of p16+/HPV+ patients under new TNM8 staging criteria.

Conclusion: Given the significantly poorer survival of p16+/HPV- OPSCCs, these data provide compelling evidence for use of an HPV-specific test for staging classification. This has particular relevance in light of potential treatment de-escalation that could expose these patients to inappropriately reduced treatment intensity as treatment algorithms evolve.
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http://dx.doi.org/10.1038/s41416-019-0414-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474272PMC
April 2019

Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15.

Structure 2019 04 31;27(4):590-605.e5. Epub 2019 Jan 31.

The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. We also designed a linear dimer (diUbV), which targeted the DUSP and catalytic domains, and exhibited enhanced specificity and more potent inhibition of catalytic activity than either UbV alone. In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor β pathway. Structural analyses revealed that three distinct UbVs bound to the catalytic domain and locked the active site in a closed, inactive conformation, and one UbV formed an unusual strand-swapped dimer and bound two DUSP domains simultaneously. These inhibitors will enable the study of USP15 function in oncology, neurology, immunology, and inflammation.
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http://dx.doi.org/10.1016/j.str.2019.01.002DOI Listing
April 2019